Current treatments have transformed HIV/AIDS from an inevitably fatal disease to one commonly managed as a chronic illness. Many children born with HIV infection, who previously suffered brief life spans, are now surviving into adulthood. This creates the need to understand more fully the obstacles these youth encounter in becoming independent, productive adults. In adults, HIV commonly is associated with impairments in memory and executive functions (such as inhibition, cognitive flexibility, and problem solving), which increase the risk of problems in day-to-day functioning, including medication nonadherence. Studies of memory and executive functions in children and youth with HIV infection are extremely limited, however, and none have included measures of prospective memory (that is, the ability to execute a future intention), which is a particularly robust predictor of daily functioning in adults with HIV. Furthermore, our current understanding of the functional impact of HIV on brain development is limited. The study proposed here would be the first to evaluate the complex interplay between development and HIV infection on memory and executive functions in the context of important functional outcomes in an effort to advance the clinical science of pediatric neuroAIDS. The study will test the hypotheses that: 1) perinatally acquired HIV is associated with deficits in memory and executive functioning;2) HIV severity and history, including age at greatest disease severity, will be associated with degree of impairment in memory and executive functioning;3) developmental change and changes in HIV severity will interact to influence these functions over time;and 4) impairments in memory and executive function contribute to problems in daily functioning (including medication adherence, academic achievement, and adaptive behavior). Using a longitudinal design to examine and control for developmental changes in these functions during adolescence, we will administer measures of verbal and nonverbal retrospective memory, prospective memory, executive functions, and medication adherence to 200 HIV-infected and 75 uninfected youth age 9-18 at two time points, two years apart. Data will be collected at eight sites participating in a large national, longitudinal study of outcomes of perinatal HIV infection, the Pediatric HIV/AIDS Cohort Study Adolescent Master Protocol, thus allowing us to examine memory and executive functioning in an efficient and cost-effective manner in the larger context of demographic, health-related, cognitive, and behavioral aspects of perinatal HIV infection. This is an important area for investigation because deficits in memory and executive function in youth with HIV could have wide-ranging effects on their acquisition of health and medication management skills, adaptive and academic functioning, behavior, and, ultimately, social and occupational outcome in adulthood. We anticipate this study will not only elucidate developmental neurocognitive aspects of perinatally acquired HIV but will also provide important information and additional tools to target areas of intervention for perinatally HIV-infected youth at risk for poor functional outcomes. PUBLIC HEALTH RELEVANCE: This study will evaluate the effect of HIV infection acquired before or during birth on the ability of children and youth to learn and recall information, remember to perform future tasks, and manage their own attention and behavior. The data will give us valuable insight into the impact of HIV on aspects of cognitive development previously not studied. The study also will examine whether problems in memory and executive functioning affect day-to-day behavior in critical areas such as medication adherence, thus providing helpful information to design effective future interventions for youth with HIV. Strengths The study captures a well-defined population of children participating already in longitudinal observational pediatric HIV research - PHACS-AMP, thus, good data on early infection, ART regimens, CD4/VL patterns/nadir, and Stage of disease are available. The collaborative team has proposed an extremely detailed assessment of verbal/functional/memory cognition (including WRAML, verbal learning, design memory, prospective memory, memory for intentions, fluency, inhibition/interference control, problem solving, working memory, cognitive flexibility, global cognition, language, and psychomotor speed) to be conducted on 200 HIV-1 infected and 75 HIV-1 uninfected children at 2.5 and 4.5 year visits- this is a large sample size with detailed assessment. The investigators have revised the application to take into account multiple comparisons Weaknesses The study is observational and involves 2 time points - more timepoints in a subset of children for a subset of evaluations would allow assessment of consistency/stability of the assessments and whether there are specific functions or groups of children with more labile changes in function/memory. Including an intervention pilot/study to enhance memory/function while characterizing